From publication WO 2006/000115 A1 is known a device and a method for the arranging of pipette or dispenser tips in a system for manipulating of liquid samples. Such a device comprises a robot manipulator for the orienting of pipette or dispenser tips in an X direction and in a Y direction running essentially perpendicular to the former, with respect to sample holders arranged in or on the system. Such devices furthermore comprise pipette or dispenser tips, which extend essentially vertically and which can be raised and lowered in a Z direction running essentially perpendicular to the X and Y directions. Furthermore, such devices comprise drive units for moving the robot manipulator and processors for controlling the movements and actions of the robot manipulator or the pipette or dispenser tips. Corresponding devices and systems are known for use in the study of genes (genomics), proteins (proteomics), for the discovery of new active substances (drug discovery) and in clinical diagnostics, such as the work platform marketed by the firm Tecan Trading AG, Seestrasse 103, CH-8708 Männerdorf under the name “Genesis Robotic Sample Processor”. This is a device for the manipulating of samples in containers and/or on specimen slides, wherein the containers and/or specimen slides are arranged on an essentially horizontal working field with a lengthwise dimension X and a transverse dimension Y and wherein the device contains robot manipulators for manipulating the samples. This manipulating can involve the taking up and/or giving out of liquids, e.g., within this X-Y field. Moreover, centrifuges and other processing stations or analysis stations can be provided, such as fluorescence readers and the like. For such work platforms it is also important to identify objects, such as test tubes, microtitration plates, and other containers holding specimens by means of a corresponding detection device, such as a barcode reader or the like: such known work platforms preferably have, for purposes of liquid handling, a robot manipulator with an arm extending in the Y direction and at least one rail extending in the X direction, on which the arm is fastened and can move back and forth in the X direction; these extend basically vertically and can be raised and lowered in the Z direction, extending basically perpendicular to the work field; and there are drive units to move the robot manipulator and processors to control the movements and actions of the robot manipulator and/or pipette tips. Furthermore, liquid samples that are being processed or studied are usually found in tubes or in the wells of microtitration plates. Such tubes are placed in suitable holders, so that each holder can accommodate a row of tubes, which are thus arranged in a line alongside each other in the Y direction, i.e., the direction of the transverse dimension of the work platform. These holders can preferably be moved on the work table. Liquid samples can also be found in the wells of microtitration plates, or be transferred by pipette from the test tubes to these wells. Usually three microtitration plates are arranged on a so-called “carrier”, which preferably can also move along the work table.
Furthermore, from publication CH 696 030 A5 there is known such a device for the manipulating of samples in containers and/or on specimen slides in the region of an X-Y field, wherein the first and the second robot manipulator can work at least the entire region of the X-Y field, practically without hindering each other. The ranges of action of the two robot manipulators can be chosen arbitrarily. The second robot manipulator, loaded with objects or not, can pass by the first robot manipulator. The moving around of various objects with the second robot manipulator, such as the shifting of active devices in the form of scanners (1D, 2D), cameras, print heads, etc., makes it possible to use the functions of this device over the entire field of the work platform. These active devices can be picked up with the second robot manipulator, even from outside the field, or be temporarily set down there. Thanks to an additional extensibility feature of the second robot manipulator, one can also service levels underneath the actual work field. Since the transporting of objects and the liquid handling are jobs that often do not take place at the same time, two independent robot manipulators are proposed.
From publication EP 1 829 613 A1 there is disclosed a storage unit for biological samples, with an essentially horizontal main standing surface and several storage chambers. In biological laboratories, especially in the laboratories of pathology institutes of universities or hospitals, biological samples such as tissue samples obtained from biopsy are very often kept as pieces of tissue in holders or as thin sections on glass specimen slides. A selection of such holders and glass specimen slides is offered, e.g., by the firm Thermo Shandon. In pharmaceutical research, chemical or biochemical compounds are routinely tested for their potential pharmaceutical activity. For this purpose, a large number of samples must be prepared in the shortest of time. Therefore, in pharmaceutical research laboratories one uses so-called “microtubes”, which contain a sufficient amount of a particular substance. In order to cope as economically as possible with the huge numbers of such microtubes, these are packed in so-called “microtube cluster racks”. For a robotized handling, it is especially preferable to use such racks as have a standing surface corresponding to the so-called “foot print” of a microtitration plate in the SBS standard (SBS=Society for Biomolecular Screening) and which is therefore often called an “SBS footprint”. In the meantime, this standard has been standardized as ANSI/SBS 1-2004 by the ANSI (American National Standards Institute). Microtube cluster racks with 96 or 384 microtubes are known, for example, by the commercial name REMP Tube Technology™. On the other hand, thin sections of fixed specimens, such as those embedded in paraffin, are routinely placed on glass slides and viewed by means of light microscope in pathology.
Moreover, from publication WO 2005/103725 A1 there is known a device for the transporting or studying of liquids in a system for working with liquid samples. Such systems include, for example, a work field extending basically horizontally in an X direction and in a Y direction at right angles to it. The device contains at least one functional element with at least one functional end, while the functional elements are oriented basically perpendicular to the work field in a Z direction. The device includes at least one tilt unit for the tiltable holding of the at least one functional element. Such a system contains at least one robot arm, on which at least one such device is fastened. Such a robot arm is then configured to move the functional element in at least a partial region of the work field and at least in the Z direction. In the technical field of liquid handling, devices for the taking up and giving out of liquid samples are known as pipettes or pipetting devices. Devices which can only be used for the giving out of liquid samples are usually called dispensers. In order to automate the pipetting process for volumes under 10 μl, one must distinguish two processes: defined taking up (aspiration) and the subsequent giving out (dispensing) of liquid samples. The pipette tip is usually moved between these two processes by the experimenter or an automatic machine, so that the place of taking up a liquid sample is often different from the place of giving it out. For a proper and reproducible taking up and/or giving out of a liquid, only the system which consists of pump (e.g., a diluter configured as a syringe pump), liquid line, and end piece (pipette tip) is significant. The giving out of a liquid with a pipette tip can occur from air or by touching of a surface. This surface can be the solid surface of a vessel into which the liquid sample is to be dispensed (“on tip touch”). It can also be the surface of a liquid located in this vessel (“on liquid surface”). A mixing process following the dispensing is recommended—especially for very small sample volumes in the nanoliter or even picoliter range—so that a uniform distribution of the sample volume in a reaction liquid is assured. From publication DE 101 16 642 C1 there is known a device with which liquids can be given out into the wells of a microtitration plate or pipetted from such containers. Work platforms or systems for the handling of liquids, such as the pipetting of liquids from containers, are known, e.g., from publication U.S. Pat. No. 5,084,242, which also proposes a tilting unit for the tiltable holding of the at least one pipetting device dispensing the liquid.
The publication DE 10 2007 018 483 A1 describes work platforms for the handling of liquids, such as the pipetting of liquids from containers and the distributing of same in the wells of a microtitration plate, which are known as “pipetting device” from publication WO 02/059626 A1 and as “device for precise docking at microplate wells” from publication EP 1 477 815 A1. It involves preferably work platforms for which a pipette tip, for example, can be automatically positioned at a certain spot. In particular, publication EP 1 477 815 A1 discloses an especially precise positioning of objects relative to the 1536 wells of a microtitration plate, so that one can avoid damaging a pipette tip, a temperature sensor, a pH probe, or another long and thin object which is supposed to be positioned in a well due to striking against the walls of the well or the surface of the microtitration plate. Furthermore, one can in this way practically rule out losses of sample and contamination of neighboring samples and of the work area. A precise docking at the wells with no danger of an unintentional touching of parts of the microtitration plate is therefore a fundamental requirement for routine working with a liquid handling system which can be used, e.g., for the automatic study of blood samples. A precise docking should be assured not only in the essentially horizontal plane of a Cartesian system of coordinates, defined by the X and Y directions; it should also be possible to position as precisely and reproducibly as possible the Z or height position of a functional tip of a long and thin object, such as a pipette tip, a temperature sensor, an optical fiber or a pH probe in a Cartesian or also in a polar system of coordinates.
Publication WO 2007/071613 A1 furthermore discloses a device for the conditioning of a system liquid for a liquid handling system, in which the following prior art is cited. Branches of industry that deal, for example, with biochemical techniques in pharmaceutical research or clinical diagnostics require systems for the processing of liquid volumes and liquid samples. Automated systems usually include a liquid handling device, such as a single pipetting device or several pipetting devices which are used at liquid containers that are situated on the work table of a work station or a so-called “liquid handling workstation”. Such work stations are often able to carry out the most diverse of chores on these liquid samples, such as optical measurements, pipetting, washing, centrifuging, incubation and filtration. One or more robots, which now operate by Cartesian or polar coordinates, can be used for the sample processing at such a work station. Such robots can carry and relocate liquid containers, such as test tubes or microtitration plates. Such robots can also be used as so-called “Robotic Sample Processor” (RSP), for example, a pipetting device for aspirating and dispensing, or dispensers for distributing the liquid samples. Preferably, such systems are guided and controlled by a computer. One decisive advantage of such systems is that large numbers of liquid samples can be processed automatically over lengthy periods of hours and days, without a human technician having to be involved in the process. Such systems can automatically process entire series of tests. Such series of tests, like the so-called “ELISA tests” (Enzyme-Linked Immuno Sorbent Assay) are now indispensable in present day clinical diagnostics and life science research. Two processes need to be basically distinguished from each other for automation in liquid handling: the defined taking up (aspiration) and the subsequent giving out (dispensing) of liquid samples. Between these processes the pipette tip is usually moved by the experimenter or an automatic machine, so that the place of taking up a liquid sample is different from its place of giving out.
EP 1 206 967 A2 describes a prior art from which it is known that drops with a volume of more than 10 μl can be very easily dispensed from the air, because the drops when properly handled with the pipette leave the pipette tip of themselves. The drop size, then, is determined by the physical properties of the sample liquid, such as surface tension or viscosity. Thus, the drop size limits the resolution of the amount of liquid being dispensed. On the other hand, the taking up and giving out, or pipetting, of liquid samples with a volume of less than 10 μl usually require instruments and techniques that guarantee the dispensing of such small samples. Systems for the separating of samples from a liquid are known as automatic pipetters. Such systems serve, e.g., to dispense liquids into the receiving wells of standard microtitration plates (commercial brand of Beckman Coulter, Inc., 4300 N. Harbour Blvd., P.O. Box 3100 Fullerton, Calif., USA 92834) or microtitration plates with 96 wells. Reduction of specimen volume (e.g., for filling of highly dense microtitration plates with 384, 864, 1536 or even more wells) is playing an increasingly important role, and great significance attaches to the accuracy of the sample volume given out. Increasing the number of samples usually also entails a miniaturization of the experiment, so that the use of an automatic pipetter becomes indispensable and special requirements need to be placed on the accuracy of sample volume, as well as the goal-seeking ability or dispensing of this automatic pipetter. More simple automatic pipetters, so-called “open systems”, connect the reservoir vessel for the liquid being pipetted to the pipette tip by a line, in which a dispenser pump can be installed. Dispenser pumps are usually designed as piston pumps. To take up (aspirate) the sample, the pump alone is placed in operation, and the pipette tip merely passes on the flow of liquid in passive manner. To give out or dispense a sample volume, the pump is then shut off or bypassed. A pipette tip in the form of a microejection pump, for example, is known from EP 0 725 267 A2, and it is used to actively separate a liquid sample. The liquid is delivered further by the hydrostatic pressure prevailing in the line between reservoir vessel and pipette tip.
In the current prior art, such as is known for example from publications WO 2006/000115 A1, WO 02/059626 A1 and EP 1 477 815 A1, it is customary to fill and wash and supply reagent to all eight wells or positions of a microtitration plate with eight equidistantly arranged hollow needles at the same time. Or, according to another prior art, these microtitration plates are filled in succession with a single hollow needle and likewise washed and aspirated in succession. This method has the drawback that, due to the filling in succession, time differences can very well occur, so that a time difference of 10 s or more can very well occur between the incubation/reaction time in the first well (reaction space) and that in the last well. This also leads to differing results. In particular, this also holds when the wells are dried for different lengths of time after the aspiration and before being filled with reagent.